A Phase 1 Dose Escalation Study of Vorinostat in Niemann-Pick C1 Disease

伏立诺他治疗尼曼-匹克 C1 病的 1 期剂量递增研究

• 批准号: 8639788
• 负责人: Frederick R. Maxfield
• 金额: $ 36.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-10 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639788
• 关键词: 18 year old; Adolescence; Adolescent; Adult; Adverse effects; Affect; Animals; Ataxia; Biochemical; Biological Markers; Blood; Blood - brain barrier anatomy; Cells; Chemistry; Childhood; Cholesterol; Clinical; Clinical Treatment; Clinical Trials; Clinical assessments; Collaborations; Cutaneous; Cyclodextrins; Data; Defect; Disease; Disease Progression; Dose; Drug Kinetics; Effectiveness; Extramural Activities; FABP3 gene; FDA approved; Foundations; Future; Glycosphingolipids; Goals; Histone Acetylation; Histone Deacetylase Inhibitor; Hour; Human; Hydroxycholesterols; Individual; Infusion procedures; Intrathecal Injections; Laboratories; Lead; Life; Lipids; Lipoproteins; Lysosomes; Malignant neoplasm of brain; Measures; Membrane Proteins; Miglustat; Monitor; Mononuclear; Mus; Mutation; National Institute of Child Health and Human Development; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oral; Oral cavity; Outcome Measure; Participant; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Plasma; Proteins; Recruitment Activity; Regimen; Regulation; Reporting; Safety; Sampling; Schedule; Severities; Sphingolipids; T-Cell Lymphoma; Therapeutic; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Universities; Vorinostat; Washington; Zolinza; base; calbindin D; cholesterol trafficking; design; early childhood; medical schools; meetings; motor impairment; mutant; open label; oxidation; primary outcome; protein function; public health relevance; research clinical testing; response; safety testing; secondary outcome; unpublished works

DESCRIPTION (provided by applicant): Niemann-Pick C (NPC) is a rare, neurodegenerative, lipid storage disease. Approximately 95% of the disease is caused by mutations in NPC1, a late endosomal/lysosomal (LE/Ly) membrane protein that functions in export of lipoprotein-derived cholesterol. Affected individuals typically present in early childhood with ataxia and progressive impairment of motor and intellectual function, and usually die in adolescence. There are currently no FDA-approved therapies for this fatal neurodegenerative disorder. Recently, we found that treatment of human NPC1 mutant cells with certain histone deacetylase inhibitors (HDACi), including Vorinostat (SAHA, Zolinza(tm)), leads to clearance of excess cholesterol and other lipids from the LE/Ly, and it corrects the overall defect in cholesterol regulation. In other unpublished work, we found that 60 of the 80 NPC1 mutants examined show significant cholesterol clearance upon treatment with the HDACi, indicating the majority or NPC1 patients may benefit from HDACi therapy. Vorinostat is an excellent candidate for clinical testing as an NPC1 therapeutic because it is orally-available, CNS-penetrant, and FDA-approved. The goal of our study is to examine Vorinostat in a Phase 1 clinical trial for the treatment of NPC1 disease. To meet this objective, we will develop a Phase 1, first-in-human, open-label, single-center, dose escalation study of Vorinostat in late adolescents and adults with NPC1 disease to establish the safety of Vorinostat for treatment of this disorder. 12 NPC1 patients (18 years and older) will be recruited for the study. Study participants will initially be dosed with 200 mg po daily for three months, followed by dose escalation to 400 mg po daily for three months. Plasma and CSF pharmacokinetics will be obtained, toxicity monitored, and clinical assessments performed. We will further evaluate the utility of peripheral and CSF disease biomarkers to guide therapy in the Phase 1 Vorinostat dose-escalation study. The primary outcome measure will be CSF 3¿,5¿,3¿- cholesten-triol, a cholesterol oxidation product that is specifically elevated in NPC1 disease and decreases in response to alleviation of neuronal cholesterol storage. Secondary outcome measures will include plasma 24(S)-hydroxycholesterol, a CNS-specific oxysterol that is elevated following correction of the neuronal cholesterol trafficking defect; CSF sphingolipid markers; CSF proteins (e.g., Calbindin D and FABP3); and histone acetylation and NPC1 protein levels in circulating mononuclear cells. These outcome measures can potentially serve as surrogate outcome measures in future Phase 2/3 HDACi trials.

描述（由适用提供）：Niemann-Pick C（NPC）是一种罕见的，神经退行性的脂质储存疾病。大约95％的疾病是由NPC1突变引起的，NPC1是一种晚期内体/溶酶体（LE/LY）膜蛋白，可在出口脂蛋白衍生的胆固醇中发挥作用。受影响的个体通常会受到共济失调和运动和智力功能的进行性损害，通常在青少年死亡。目前，这种致命的神经退行性疾病尚无FDA批准的疗法。最近，我们发现，用某些组蛋白脱乙酰基酶抑制剂（HDACI）（包括伏诺替纳斯塔特（Saha，Zolinza（TM）））对人NPC1突变细胞进行处理，可清除过量的胆固醇和其他脂质，从LE/LE/LE/LE/ly/couse纠正胆固醇法规的整体缺陷。在其他 未发表的工作，我们发现检查的80个NPC1突变体中有60个在用HDACI治疗时显示出明显的胆固醇清除率，表明大多数或NPC1患者可能会受益于HDACI疗法。 Vorinostat是作为NPC1治疗的临床测试的绝佳候选者，因为它是口服的，CNS-PENETRANT和FDA批准的。我们研究的目的是在1阶段临床试验中检查伏地的治疗，以治疗NPC1疾病。为了满足这一目标，我们将开发一种第1阶段的人类，开放标签，单中心，剂量升级研究，对晚期青少年和NPC1疾病的成年人进行伏地的剂量升级研究，以确立伏地替代治疗这种疾病的安全性。该研究将招募12名NPC1患者（18岁以上）。研究参与者最初将每天用200毫克PO进行三个月的时间，然后剂量升级至400毫克PO，持续三个月。将获得血浆和CSF药代动力学，监测毒性以及进行临床评估。我们将进一步评估外周和CSF疾病生物标志物的实用性，以指导第1阶段Vorinostat剂量降低研究。主要结局指标将是CSF 3？，5€，3¿-胆固醇 - 胆固醇氧化物产物，在NPC1疾病中特异性升高，并且响应于减轻神经胆固醇的储存而降低。次要结局指标将包括血浆24（S） - 羟基胆固醇，羟基胆固醇是一种CNS特异性氧甲醇，在校正神经元胆固醇运输缺陷后升高； CSF鞘脂标记； CSF蛋白（例如Calbindin D和Fabp3）；循环单核细胞中的组蛋白乙酰化和NPC1蛋白水平。这些结果度量可能有可能作为未来2/3阶段HDACI试验的替代结果度量。